Abstract. Diabetic neuropathic pain (DNP) is one of the most common and difficult to treat complications of diabetes [1, 2]. Current therapies [3-10] do not directly address the fact that pain sensation is processed in the brain [10-13] and most act at the neuropathy site (i.e., in the periphery), although DNP patients also have a central pain component due to their injury [10-13]. DNP symptomatology correlates with chronic pain induced changes in brain activity and/or structure [13-19]. Non-Invasive Brain Stimulation (NIBS) has been successfully applied for the treatment of chronic pain in some disease states, where treatment induced changes in brain activity revert maladaptive plasticity associated with the perception/sensation of chronic pain [20-23]. However, the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), have shown limited, if any, efficacy in treating neuropathic pain and DNP [12, 24-30]. It has been postulated that limitations in these techniques' focality, penetration, and targeting control limit their therapeutic efficacy [31-35]. Electrosonic Stimulation (ESStim?) is an improved NIBS modality that overcomes the limitations of other technologies by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue [36]. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively treat DNP. First in Phase I, to assess the feasibility of the proposed work, we will follow 20 DNP patients after giving a fixed dose of ESStim for 5 consecutive days, 20 min/day (10 SHAM ESStim, 10 ESStim?). We will administer a battery of safety, pain, quantitative sensory testing (QST), motor function, and global self-assessments (e.g., QOL), and actigraphy measures in the patients, evaluated over the treatment period and for at least six weeks following the last treatment session. Next in Phase II, we will follow 40 DNP patients (20 ESStim, 20 SHAM) after giving a fixed dose of stimulation for 5 consecutive days, 20 min/day, followed by three weeks of bi- weekly stimulation, 20 min/day (11 total stimulations). We will evaluate these patients with the same battery of assessments validated in Phase I, and compare the efficacy of the tested interventions for at least eight weeks following the last treatment session. In parallel with the DNP treatments, we will build MRI derived models of the stimulation fields in the heads (electric and acoustic field models) of the DNP patients to calculate the stimulation field characteristics at the brain target sites. Multivariate linear and generalized linear regression models will then be built and evaluated to predict the DNP patient outcomes related to pain, physical function, and psychosocial assessments as a function of baseline disease characteristics and the MRI based dosing models. The computational work will be combined to develop an optimized DNP ESStim dosing model. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to optimize ESStim? for treatment of central pain in DNP.